Promoting Disposal of Left-Over Opioids After Surgery in Rural Communities: A Qualitative Description Study

Background Patients rarely dispose of left-over opioids after surgery. Disposal serves as a primary prevention against misuse, overdose, and diversion. However, current interventions promoting disposal have mixed efficacy. Increasing disposal in rural communities could prevent or reduce the harms caused by prescription opioids. Aims Identify barriers and facilitators to disposal in the rural communities of the United States Mountain West region. Methods We conducted a qualitative description study with 30 participants from Arizona, Idaho, Montana, Nevada, Oregon, Utah, and Wyoming. We used a phronetic iterative approach combining inductive content and thematic analysis with deductive interpretation through the Precaution Adoption Process Model (PAPM). Results We identified four broad themes: (a) awareness, engagement, and education; (b) low perceived risk associated with nondisposal; (c) deciding to keep left-over opioids for future use; and (d) converting decisions into action. Most participants were aware of the importance of disposal but perceived the risks of nondisposal as low. Participants kept opioids for future use due to uncertainty about their recovery and future treatments, breakdowns in the patient–provider relationship, chronic illness or pain, or potential future injury. The rural context, particularly convenience, cost, and environmental contamination, contributes to decisional burden. Conclusions We identified PAPM stage-specific barriers to disposal of left-over opioids. Future interventions should account for where patients are along the spectrum of deciding to dispose or not dispose as well as promoting harm-reduction strategies for those who choose not to dispose.

Differential sialic acid content in adult and neonatal fibrinogen mediates differences in clot polymerization dynamics

Neonates possess a molecular variant of fibrinogen, known as fetal fibrinogen, characterized by increased sialic acid, a greater negative charge, and decreased activity compared to adults. Despite these differences, adult fibrinogen is used for treatment of bleeding in neonates, with mixed efficacy. In order to determine safe and efficacious bleeding protocols for neonates, more information on neonatal fibrin clot formation and the influence of sialic acid on these processes is needed. Here, we examine the influence of sialic acid on neonatal fibrin polymerization. We hypothesized that the increased sialic acid content of neonatal fibrinogen promotes fibrin B:b knob hole interactions and consequently influences the structure and function of the neonatal fibrin matrix. We explored this hypothesis through analysis of structural properties and knob:hole polymerization dynamics of normal and desialylated neonatal fibrin networks and compare to those formed with adult fibrinogen. We then characterized normal neonatal fibrin knob:hole interactions by forming neonatal and adult clots with either thrombin or snake-venom thrombin like enzymes (SVTLEs) that preferentially cleave fibrinopeptide A or B. We determined that sialic acid content of neonatal fibrinogen is a key determinant of resulting clot properties. Experiments analyzing knob:hole dynamics indicated typical neonatal fibrin clots are formed with the release of more fibrinopeptide B and less fibrinopeptide A than adults. After the removal of sialic acid, fibrinopeptide release was roughly equivalent between adults and neonates indicating the influence of sialic acid on fibrin neonatal fibrin polymerization mechanisms. These results could inform future studies developing neonatal specific treatments of bleeding.

Efficacy of tocilizumab in COVID-19: A review of the current evidence

As cases of coronavirus 2019 (COVID-19) keep rising, reported deaths are increasing. Public health measures have been implemented with mixed efficacy. As vaccines are becoming more widely available and accessible globally, treating critically ill COVID-19 patients remains an issue with only dexamethasone found to be therapeutically effective to date. However, trials studying the efficacy of IL-6 inhibitors, namely tocilizumab have been underway with promising results. This paper is a narrative review that aims to review the current evidence provided by randomized clinical trials (RCT) for the use of tocilizumab in COVID-19. Electronic database searches were carried out in Medline, PubMed, Embase, Google Scholar, and ongoing clinical trial registries with the period set from January 1, 2020 to February 20, 2021. Prepublication manuscripts were found using the pre-print repository medRxiv. Keywords included “COVID-19,”“coronavirus,”“SARS-CoV-2,”“sepsis,”“pneumonia,”“cytokine storm,”“cytokine release syndrome,”“IL-6 inhibitors,” and “tocilizumab,” as exact phrases, and a combination of subject headings according to databases syntax. Only trials with a clear and well-defined methodology, at least 100 patients recruited, and which have had results published either after peer review or in pre-print were included. In hospitalized patients with severe COVID-19, who are hypoxic and have a CRP ≥ 75 mg/L, the current evidence favors the use of a combination of tocilizumab and corticosteroids to reduce mortality, among other clinical benefits. There is also overwhelming evidence of the good safety profile of tocilizumab with only few cases of neutropenia reported with a decrease in infection rates. Tocilizumab is currently thought to work through the inhibition of IL-6 receptors (IL-6R), preventing downstream activation of pro-inflammatory reactions and cytokine release syndrome.

(Re)contextualizing the Trauma to Prevent or Treat PTSD-Related Hypermnesia

A cardinal feature of Post-traumatic stress-related disorder (PTSD) is a paradoxical memory alteration including both intrusive emotional hypermnesia and declarative/contextual amnesia. Most preclinical, but also numerous clinical, studies focus almost exclusively on the emotional hypermnesia aiming at suppressing this recurrent and highly debilitating symptom either by reducing fear and anxiety or with the ethically questionable idea of a rather radical erasure of traumatic memory. Of very mixed efficacy, often associated with a resurgence of symptoms after a while, these approaches focus on PTSD-related symptom while neglecting the potential cause of this symptom: traumatic amnesia. Two of our preclinical studies have recently demonstrated that treating contextual amnesia durably prevents, and even treats, PTSD-related hypermnesia. Specifically, promoting the contextual memory of the trauma, either by a cognitivo-behavioral, optogenetic or pharmacological approach enhancing a hippocampus-dependent memory processing of the trauma normalizes the fear memory by inducing a long-lasting suppression of the erratic traumatic hypermnesia.

THE USE OF PHYSICAL ACTIVITY OUTCOMES IN REHABILITATION INTERVENTIONS FOR LOWER LIMB AMPUTEES: A SYSTEMATIC REVIEW

BACKGROUND: Interventions which have focused on improving the physical activity of individuals with lower limb amputation can be mostly categorized into behavioural-based and prosthetic-based interventions. The aim of this review was to assess the quality of these interventions, and to identify the key gaps in research in this field. METHODOLOGY: The databases of Scopus, Pubmed, Embase, Medline and Web of Science were searched between September and December of 2019 for articles relating to physical activity, amputees and interventions. Articles were assessed quantitively based on internal validity, external validity and intervention intensity. FINDINGS: Sixteen articles (5 behavioural, 11 prosthetic) were assessed. Both approaches had comparable methodological quality and mixed efficacy for producing a significant change in physical activity outcomes. Almost all interventions used a simplistic measurement of activity as their outcome. CONCLUSIONS: There is an insufficient amount of studies to assess the overall efficacy of behavioural interventions in regard to how they impact on physical activity behaviour. However, the increase of quality of the methodology in the more recent studies could indicate that future interventions will retain similar levels of quality. Prosthetic interventions have shown no major improvement in efficacy compared to similar reviews and may need to utilise more advanced prosthetic components to attain significant changes in physical activity. Activity outcomes should expand into more complex activity measurements to properly understand the physical activity profile of people with lower limb amputation. Layman’s Abstract: The purpose of this review was to identify original research which tried to improve the physical activity behaviours of individuals with lower extremity amputation. Through multiple databases, the review article identified a mixture of 5 behavioural and 11 prosthetic-based interventions which aligned with the search criteria of the review. The behavioural-based interventions used behavioural change techniques controlled by healthcare professionals to try and promote a change in physical activity behaviours. The prosthetic-based interventions employed a prosthetic component, with the intention being that if the prosthetic component had superior design, the individual would feel more encouraged to be physically active. This review article concludes that, prosthetic interventions do not appear to have a consistent significant impact on the physical activity behaviours, and though behavioural interventions also had mixed efficacy, there were not enough interventions of their design to make a conclusive statement. Article PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/33931/26330 How To Cite: Jamieson A.G., Murray L., Buis A. The use of physical activity outcomes in rehabilitation interventions for lower limb amputees: A systematic review. Canadian Prosthetics & Orthotics Journal. 2020;Volume3, Issue1, No.2. https://doi.org/ 10.33137/cpoj.v3i1.33931 Corresponding Author: Dr. Arjan Buis,Department of Biomedical Engineering, University of Strathclyde, Wolfson Centre, 106 Rottenrow, Glasgow, G4 0NW, Scotland, UK.E-Mail: [email protected]: https://orcid.org/0000-0003-3947-293X

Effects of L-DOPA on gene expression in the frontal cortex of rats with unilateral lesion of midbrain dopaminergic neurons

The development of Parkinson’s disease (PD) causes dysfunction of the frontal cortex, which contributes to hallmark motor symptoms and is regarded as one of the primary causes of the affective and cognitive impairments observed in PD. Treatment with L-DOPA alleviates motor symptoms but has mixed efficacy in restoring normal cognitive functions, which is further complicated by the psychoactive effects of the drug. In this study, we investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We performed an RNA-seq analysis of gene expression in the frontal cortex of rats with 6-hydroxydopamine (6-OHDA)-induced unilateral dopaminergic lesion that were treated with L-3,4-dihydroxyphenylalanine (L-DOPA), for 2 weeks. We used analysis of variance to identify differentially expressed genes and found 48 genes with significantly altered transcript abundance after L-DOPA treatment. We also performed a weighted gene coexpression network analysis (WGCNA), which resulted in the detection of 5 modules consisting of genes with similar expression patterns. The analyses led to three primary observations. First, the changes in gene expression induced by L-DOPA were bilateral, although only one hemisphere was lesioned. Second, the changes were not restricted to neurons but also appeared to emerge in immune or endothelial cells. Finally, comparisons with databases of drug-induced gene expression signatures revealed multiple nonspecific effects, which indicates that a part of the observed response is a common pattern activated by multiple types of pharmaceuticals in different target tissues. Taken together, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment.

Using RNA Editing and ADARs to Increase Cell Sensitivity to Interferon Chemotherapies

Background and Hypothesis: During viral infection, viral double stranded RNAs (dsRNAs) are bound by and activate pattern recognition receptors (PRRs). Activated PRRs signal several downstream cellular events, including activating transcription of interferon (IFN). IFN-β can bind to cellular receptors and increase transcription of PRRs, interferon stimulated genes (ISGs), activate Protein Kinase R (PKR) and trigger apoptosis. The ability of IFN to trigger apoptosis makes it a potential chemotherapeutic. However, IFN therapy has had mixed efficacy in inducing tumor cell apoptosis. One mechanism for this failure may be intrinsic mechanisms that prevent dsRNA from binding to and activating PRRs. ADAR1 binds to dsRNA and catalyzes deamination of adenosine to inosine, a process known as RNA editing. Normally, ADAR1 inhibits cellular dsRNAs from initiating the IFN response. Recent studies have shown ADAR1 is overexpressed in several cancers and contributes to oncogenic phenotypes, suggesting inhibition of ADAR1 may increase sensitivity to IFN-β. The Hundley lab recently identified an inhibitor of ADAR1 called ADAR3. ADAR3 has no deaminase activity and is highly expressed in glioblastoma (GBM) tumors. We hypothesize that ADAR3 expressing GBM cells should exhibit a greater antiproliferative effect in response to IFN-b treatment compared to control. Experimental Design or Project Methods: An MTT assay was conducted in which U87 ADAR3 +/- cell lines were exposed to IFN-β after 24 hours. Cell viability was measured for 3 days post-treatment. Results: U87 ADAR3 + cells are more sensitive to IFN-β treatment (n=2 biological replicates, p-value= 0.04). Conclusion and Potential Impact: The results suggest a mechanism to enhance IFN therapy for patients with ADAR3 expressing GBM.